The following discussion of the background to the invention is intended to facilitate an understanding of the present invention. However, it should be appreciated that the discussion is not an acknowledgment or admission that any of the material referred to was published, known or part of the common general knowledge in any jurisdiction as at the priority date of the application.
In the design and development of novel drug delivery systems, polymeric micelles, for instance, have attracted considerable attention due to their potential for use as drug delivery vehicles for anti-cancer drugs to target tumor tissues. Briefly, a micelle is an aggregate of amphiphilic or surfactant molecules dispersed in a liquid colloid. Each of the amphiphilic/surfactant molecules has a hydrophilic “head” end and a hydrophobic “tail” end. The tails of the micelle may include hydrocarbon groups, and the heads of the micelle may include charged (anionic or cationic) groups or polar groups. In a polar solvent such as an aqueous liquid, an aggregate of the micelle molecules typically form a normal micelle with the hydrophilic head ends extending outward and in contact with the surrounding solvent, sequestering the hydrophobic tail ends in the micelle centre, thereby forming the hydrophobic core. The polymeric micelles are generally formed from the self-assembly of amphiphilic block copolymers in an aqueous environment. It is known that polymeric micelles allow for enhanced accumulation of anti-cancer drug (i.e. enhanced drug loading) at tumor sites due to the enhanced permeability and retention (EPR) effect resulting from the leakiness of tumor vasculature (H. Maeda, Adv. Enzyme Regul. 2001, 41, 189-207). In addition, the outer hydrophilic shell of the micelles prevents the adhesion of proteins and reduces the uptake of micelles by the reticuloendothelial system (RES), thereby prolonging the blood circulation of micelles in the body (A. Lavasanifar et al, Adv. Drug. Deliv. Rev. 2002, 54, 169-190).
Over the past two decades, many groups have developed polymeric micelles comprising of amphiphilic block copolymers of poly(ethylene glycol) (“PEG” for short) and hydrophobic polymers such as poly(α/β-aspartic acid) block copolymer (“PEG-P(Asp)” for short), poly(L-glutamate) block copolymer (“PEG-P(Glu)” for short) and poly(L-lysine)-succinate (N. Nishiyama et al, Langmuir, 1999, 15, 377-383, N. Nishiya et al, Bioconjugate Chem. 2003, 14, 449-457 and A. A. Bogdanov et al, Bioconjugate Chem. 1996, 7, 144-149). Different methods have been developed to encapsulate anti-cancer drugs, such as doxorubicin, cisplatin and proteins, within the micellar core (H. M. Aliabadi, Polymeric Micelles for Drug Delivery, 2006, 3, 139-162). Furthermore, in-vivo studies have demonstrated that these micelles have higher anti-tumor efficacy because the drugs encapsulated in the polymeric micelles accumulate in tumor tissues more effectively than the free drugs themselves (N. Nishiyama, Cancer Research, 2003, 63, 8977-8983). However, one problem prevalent in these polymeric micelle systems is that the drug loading in such micelles is often very low. In other words, the drug only constitutes a small proportion of the polymeric micelle by weight.
Although the above discussion focuses on polymeric micelles, other drug delivery systems such as matrix delivery systems and drug targeting systems also face similar problem of low drug loading for effective drug delivery.
It is therefore desirable to provide for anti-cancer agent delivery vehicles that overcomes, or at least alleviates, one of the above mentioned problems.